Confirmed tumor response by molecular subtype in patients with metastatic breast cancer: Sub-analysis from a phase 3 clinical study comparing oral paclitaxel and encequidar to IV paclitaxel.

1073 Background: Paclitaxel, a foundation treatment in MBC, is hydrophobic and must be formulated for IV administration with Cremophor EL, increasing the risk of infusion reactions and necessitating pre-treatment with corticosteroids and antihistamines. Paclitaxel cannot be administered orally because it is a substrate for P-gp. The oral bioavailability of paclitaxel is improved when administered 1 hour after the highly selective, potent, and minimally absorbed P-gp inhibitor encequidar. As oral paclitaxel is Cremophor-free there is no need for pretreatment for infusion reactions. While targeted therapies have improved outcomes in patients with HER2+ tumors there is still an unmet need for therapies that prolong survival with reduced toxicity across all tumor subtypes. Methods: A phase 3, open-label, randomized, multicenter study in women with histologically- or cytologically-confirmed MBC for whom treatment with IV paclitaxel monotherapy had been recommended by their oncologist randomized 402 patients 2:1 to either oral paclitaxel and encequidar (oPac+E) or IV paclitaxel (IVPac). Oral paclitaxel 205 mg/m2 was administered once daily for 3 consecutive days, weekly. Encequidar 12.9 mg was administered 1 hour before each dose of oral paclitaxel. IV paclitaxel 175 mg/m2 was infused over 3 hours on day 1 of every 3 weeks. Results: In the ITT population oPac+E was superior to IV paclitaxel with a confirmed tumor response rate of 35.8% vs 23.4% for IVPac: a difference of 12.4% (p = 0.0107). A post-hoc subgroup efficacy analysis was conducted based on tumor subtypes, however, the study was not powered to detect statistical differences within these subgroups. Patients in the HR+/HER2- subgroup had a better tumor response to oPac+E (44.8% vs 21.4% IVPac-response rate difference of 23.4%) as did patients in the TNBC (30.5% vs 20.2%-response rate difference of 10.3%) subgroup. Responses were similar (49% vs 47.4% IVPac) in the HER2+ subgroup. Patients with unknown HER2 status receiving oPac+E had a 58.8% response rate vs 14.3% with IVPac (response rate difference of 44.5%). Conclusions: oPac+E is the first oral taxane to demonstrate superiority in radiologically confirmed tumor response rate compared to IVPac in a group of 402 women with metastatic breast cancer. Patients with HR+/HER2-, TNBC, and Unknown subtypes responded considerably better to oPac+E vs IVPac—especially the HR+/HER2- subtype which represented 63% of the patients treated with oPac+E and 55% of the patients treated with IVPac. Clinical trial information: NCT 02594371 .

Oral paclitaxel with encequidar compared to intravenous paclitaxel in patients with advanced cancer: a randomised crossover pharmacokinetic study.

Background and purpose: Paclitaxel is a widely used anti-neoplastic agent but has low oral bioavailability due to gut extrusion by P-glycoprotein (P-gp). Oral paclitaxel could be more convenient, less resource intensive, and more tolerable than intravenous administration. Encequidar (HM30181A) is a novel, minimally absorbed gut specific P-gp inhibitor. We tested whether administration of oral paclitaxel with encequidar (oPac+E) achieved comparable AUC to intravenous paclitaxel (IVP) 80mg/m2. Experimental approach: We conducted a multi-centre randomised crossover study with two treatment periods. Patients (pts) with advanced cancer received either oral paclitaxel 615mg/m2 divided over three days and encequidar 15mg orally one-hour prior, followed by IVP 80mg/m2, or the reverse sequence. PK blood samples were taken up to day 9 for oPac+E and day 5 for IVP. Key Results: 42 pts were enrolled; 35 completed both treatment periods. AUC0-∞was 5033.5 +/- 1401.1 ng.h/mL for oPac+E and 5595.9 +/- 1264.1 ng.h/mL with IVP. The geometric mean ratio (GMR) for AUC was 89.5% (90% CI 83.9-95.5). Mean absolute bioavailability of oPac+E was 12%. PK parameters did not change meaningfully after 4 weeks administration of oPac+E in an extension study. G3 treatment emergent adverse events occurred in 7 (18%) pts with oPac+E and 2 (5%) with IVP. 75% of pts preferred oPac+E over IVP. Conclusion and Implications: GMR for AUC was within the predefined acceptable range of 80%-125% for demonstrating equivalence. oPac+E is tolerable and there is no evidence of P-gp induction with repeat administration. With further study, oPac+E is a candidate to replace IVP.

The Length of Disulfide Bond-Containing Linkages Impacts the Oral Absorption and Antitumor Activity of Paclitaxel Prodrugs-Loaded Nanoemulsions

Rational design of oral paclitaxel (PTX) preparations is still a challenge. Many studies focus on developing PTX-loaded nanoemulsions (NEs) for oral administration. Unfortunately, PTX has poor affinity with the commonly...